This revised application for a Midcareer Investigator Award in Patient-Oriented Research (K24) seeks to provide the candidate, a neuroradiologist and nuclear medicine physician with existing extensive positron emission tomography (PET) imaging experience, with support for focused research and additional training in mechanisms underlying the interface between late-life depression and dementia, and for mentoring activities. This award will be applied to an NIMH-funded R01 (MH59945) investigating central serotonergic function in late-life depression with PET. Depression in late life carries an increased risk of dementia and brittle response to treatment. The R01-supported Research Plan entails quantitative imaging of two important markers strongly implicated in depression and mechanisms of antidepressant pharmacotherapy: the 5-HT1A receptor and the 5-HT transporter, PET imaging of these two sites in untreated elderly patients with major depression and age, gender-matched controls will test a model of late-life depression, including our hypotheses that 5-HT1A binding in the prefrontal cortex will be predictive of treatment responsivity and hippocampal 5-HT1A binding will correlate with baseline cognitive impairment and, more importantly, dementia risk. Career Development will incorporate training in basic mechanisms and clinical aspects of Alzheimer's disease. Since genetic studies will likely play a substantial role in future investigative efforts aimed at identifying persons at high risk for developing dementia and assessing antidepressant treatment responsivity, the candidate seeks training that will enable her to be an educated member of a multi-disciplinary research team using both genetic and a variety of in vivo imaging markers to study dementia risk and its link to late-life depression. These dements are complemented by a Mentoring Plan supportive of the candidate's further development as a mentor of both M.D. and Ph.D. trainees in the conduct of patient-oriented neuroimaging research. This K24 application extends the PI's NIMH-supported level I K-award (K07) work in PET imaging of the 5-HT system in late-life mental disorders. The purpose of the current proposal is to provide the candidate with 25% protected time to: 1) expand her efforts in mentoring junior clinical neuroscientists in neuroimaging, and 2) to acquire advanced training that will meet the challenges of designing and implementing future large-scale investigative efforts to apply specialized PET imaging techniques to studies of brain aging. [unreadable] [unreadable]